Due to the clinical success of cis-diamminedichloroplatinum(II) (cisplatin) for cancer treatment, there has been many research efforts on investigating metal-based anti-cancer drugs, including the cisplatin analogues and ruthenium (II)-arene complexes which target DNA [Sadler, P. J. et al. Curr. Opin. Chem. Biol. 2008, 12, 197]. However, these drugs often showed low selectivity between normal cells and cancer cells, resulting in severe side effects accompanied with the treatment. Recently, the deficiencies in DNA mismatch repair (MMR) have been shown to be correlated with cancerous transformations with cancer cells generally showing a high frequency of mismatched sites due to their deficiencies in MMR [Loeb, L. A. A. et al. Cancer Res. 2001, 61, 3230]. As a result, DNA mismatched sites have become novel diagnostics and therapeutics targets for cancer treatment because of their high occurring rates in cancer cells.
Re-sequencing is a universal method for the detection of DNA mismatched site [Zhou, W. et al. Curr. Opin. Oncol. 2003, 15, 50]. It is an expensive method because of complicated data processing and material consumption. Development of simple and efficient detection methods, such as designing luminescent probes toward mismatched DNA is needed. Recently, Barton and coworkers discovered that the d6 octahedral metal complex, Rh(bpy)2chrysi3+(chrysi=5,6-chrysenequinone diimine, bpy=2,2′-bipyridine), can preferentially bind to thermodynamically destabilized mismatched site through bulky chrysi ligand [Barton, J. K. et al. J. Am. Chem. Soc. 1997, 119, 12986]. The sterically bulky ligand are thought to hinder the insertion of Rh complex toward well-matched DNA, leading to good selectivity. However, due to the non-emissive d-d ligand field (LF) state, which is at a comparable energy level to those of the luminescence excited states of rhodium(III) complexes, no significant luminescence signals can be observed at room temperature, thus limiting the use of rhodium(III) complexes as luminescent probes. The same author reported another d6 octahedral ruthenium(II) comple also containing sterically bulky ligands for targeting mismatched DNA. It was found that Δ-[Ru(bpy)2dppz]2+ showed more significant emission enhancement toward defective DNA than matched DNA [Barton, J. K. et al. Inorg. Chem. 2012, 51, 12511].
Metal complexes having d8 electron configuration and thus square planar geometry are also known to bind to DNA through intercalation [Newkome, G R, et al Chem. Rev., 2008, 108, 1834-1895]. The binding with secondary DNA can be rendered specific providing appropriate ligand design, examples of which are luminescent platinum(II) complexes selectively targeting G-quadraplex DNA and differentiating between dsRNA and dsDNA [Che, C.-M. et al. J. Am. Chem. Soc. 2009, 131, 1835, Che, C.-M. et al. Angew. Chem. 2014, 126, 10283]. However, the field of using d8 square planar metal complexes to target matched DNA still in its infancy.
There is a need, therefore, for new methods of targeting matched DNA using d8 square planar metal complexes.